This invention relates to novel branched adamantyl, noradamantyl aryl and aralkylpiperazines having serotonin 5-HT1A activity. More particularly, the present invention relates to compounds and methods using them to provide neuroprotection and prevent, inhibit or limit processes of neurodegeneration in mammals.
Compounds having selective agonist and partial agonist activity at the 5-HT1A receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone, Buspar(copyright), U.S. Pat. No. 3,717,634). Evidence generated over the past 20 years supports the hypothesis that 5-HT1A agonists and partial agonists may find use in the treatment of several diseases such as anxiety, depression, schizophrenia, sexual dysfunction, cognitive deficits resulting from neurodegenerative diseases like Alzheimer""s Disease, nausea and vomiting, sleep disorders, pain, obesity, pain, addiction/withdrawal and in the treatment of prostate cancer (for recent reviews, see: Rasmussen, K. and Rocco, V. P., Recent Progress in Serotonin (5-HT)1A Receptor Modulators, In: Annual Reports in Medicinal Chemistry, Volume 30, Bristol, J. A., ed., Academic Press, New York, 1995, pp. 1-9; Schaus, J. M. and Bymaster, F. P., Latest Developments in Serotonin Receptor Modulation, In: Annual Reports in Medicinal Chemistry, Volume 33, Bristol, J. A., ed., Academic Press, New York, 1998, pp. 21-30).
More recent evidence now indicates that 5-HT1A agonists and partial agonists act in other disease states and conditions by virtue of their ability to inhibit the release of glutamate. 5-HT1A agonists and partial agonists may be used to treat conditions arising from the dysfunction of the glutamate neurotransmitter system or the aberrant release of glutamate.
Glutamate is the predominant neurotransmitter in the central nervous system and it plays an important role in neuroplasticity. As such, excessive extracellular levels of glutamate have been associated with the pathophysiology of both acute neurodegenerative disorders such as stroke, transient ischemic attack and spinal/brain trauma, as well as chronic neurodegenerative disorders such as epilepsy, Alzheimer""s Disease, amyotrophic lateral sclerosis, Huntington""s Disease, Parkinson""s Disease, AIDS dementia and retinal diseases (Holt, W. F. et al., Glutamate in Health and Disease: The Role of Inhibitors. In: Neuroprotection in CNS Diseases. Bar, P. R. and Beal, M. F., ed., Marcel Dekker, Inc., New York 1997, pp. 87-119; Engelsen, B. A. et al., Alterations in Excitatory Amino Acid Transmitters in Human Neurological Disease and Neuropathology. In: Neurotoxicity of Excitatory Amino Acids. Guidotti, A., ed., Raven Press Ltd., New York 1990, pp. 311-332; Ince, P. G. et al., The Role of Excitotoxicity in Neurological Disease. Res. Contemp. Pharmacother. 1997, 8, 195-212; Meldrum, P. S. The Glutamate Synapse as a Therapeutical Target: Perspective for the Future. Prog. Brain. Res. 1998, 441-458). Compounds which inhibit or attenuate the release of glutamate represent potential neuroprotective agents for the treatment of ischemia resulting from stroke, transient ischemic attack, brain/spinal trauma and fetal hypoxia (Koroshetz, W. J. and Moskowitz, M. A., Emerging Treatment for Stroke in Humans. Trends in Pharmacol. Sci 1996, 17, 227-233; Dunn, C. D. R. Stroke: Trends, Treatments and Markets. Scrip Reports, PJB Publications, Richmond 1995). Ischemia can also result from surgery where the blood flow must be halted for a period of time (e.g., cardiac by-pass surgery) due to the resulting anoxia and hypoglycemia (Arrowsmith, J. E. et al., Neuroprotection of the Brain During Cardiopulmonary Bypass. A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients, Stroke 1998, 29, 2357-2362, and references cited within).
Serotonin 5-HT1A receptors are located in brain areas which are highly sensitive to ischemia, such as the hippocampus and cerebral cortex. Activation of this receptor subtype results in neuronal hyperpolarization and a concomitant inhibition of neuronal activity (DeVry, J. 5-HT1A Receptor Agonists: Recent Developments and Controversial Issues. Psychopharmacology 1995, 121, 1-26). Moreover, it has been demonstrated that 5-HT1A receptor agonists and partial agonists are able to attenuate glutamate release, most likely through activation of 5-HT1A receptors located on glutamatergic terminals (Matsuyama, S. et al., Regulation of Glutamate Release via NMDA and 5-HT1A Receptors in Guinea Pig Dentate Gyrus. Brain Res. 1996, 728, 175-180) and that a number of 5-HT1A agonists and partial agonists exert neuroprotective properties in vivo (DeVry, J. et al., BAY x 3702, Drugs of the Future 1997, 22, 341-349, and references cited within).
Therefore, in addition to its well established potential therapeutic applications, compounds which possesses 5-HT1A agonist or partial agonist activity may be used as neuroprotective agents as well as a means for treating psychosis.
Preclinical models, neurochemical hypotheses and brain localization have predicted a number of potential therapeutic targets for serotonin 5-HT1A antagonists as well. These targets include the cognitive deficits observed in Alzheimer""s Disease, anxiety, depression, schizophrenia and urinary incontinence (for a review see Schechter, L. E. and Kelly, M. G., An Overview of 5-HT1A Receptor Antagonists: Historical Perspective and Therapeutic Targets, in Serotoninxe2x80x94Current Drugs ID Research Alert 1997, 2, 299-309).